Tuesday, June 25, 2013

"Reasons to Believe" in ENCODE

Fazale "Fuz" Rana is a biochemist at Reasons to Believe". He and his colleagues are Christian apologists who try to make their faith compatible with science. Fuz was very excited about the ENCODE results when they were first published [One of the Most Significant Days in the History of Biochemistry]. That's because Christians of his ilk were very unhappy about junk DNA and the ENCODE Consortium showed that all of our genome is functional.1

Fuz is aware of the fact that some people are skeptical about the ENCODE results. He wrote a series of posts defending ENCODE.

The second post is a lengthy discussion of the meaning of "function." Rana is happy with the ENCODE definition of "function" because it's a "causal definition" based on things like, transcription, the binding of transcription factors, DNA methylation etc. He says,

The implied assumption is that if a sequence is involved any of these processes—all of which play well-established roles in gene regulation—then the sequences must have functional utility.

He doesn't discuss whether transcription of known pseudgogenes means that the pseudogene has a function or whether the "function" of a random accidental binding site has any biological significance.

The third post is the one that's most interesting because it highlights some basic flaws in fact and logic. These flaws are not confined to creationists, many scientists make the same errors.

Let's look at Fuz Rana's third post from May 13, 2013. He discusses four significant objections to the ENCODE results.

1. Logical Errors in Assigning Function

According to Fuz Rana, the skeptics accuse the ENCODE Consortium of faulty logic when it comes to assigning functional parts of the genome. If part of the genome is expressed to produce a functional product (RNA or protein) then it has to be transcribed. In terms of logic, if the DNA is functional (F) then it is transcribed (T). In other words, if F, then T.

The ENCODE logic goes like this ....

If F, then T
T is observed
Therefore, F

This is faulty logic since the premise doesn't exclude the fact that T (transcription) could occur in the absence of F (function). Fuz Rana is specifically addressing an objection from Dan Graur ...

Graur’s team argues this conclusion is invalid. For example, it is possible that the transcription factor could bind randomly to DNA sequences that do not serve as promoters or enhancers, or in any other functional role. In other words, to conclude that DNA sequences are functional if they bind transcription factors is to affirm the consequent. Graur’s group believes the ENCODE Project committed this logical error for all the assays they performed when assigning function to DNA sequences.

To my mind, Graur's objection is a devastating criticism of the ENCODE results, especially since we know for a fact that transcription factors bind to nonfunctional DNA.

But to Fuz Rana it's all a question of philosophy.

In my opinion this concern is not nearly as problematic as Graur’s team makes it out to be. They conflate deductive reasoning with inductive; yet scientific investigations rely on induction, not deduction. While Graur’s group rightly points out that affirming the consequent is a logical fallacy when engaged in deductive reasoning, this error doesn’t apply to inductive reasoning. Induction produces conclusions that are probabilistic though not certain.

Let’s return to the example of transcription factor binding to DNA. As already noted, if a DNA sequence serves as an enhancer or promoter, it will bind a specific set of transcription factors. If a scientist then observes transcription factors binding to DNA, it is reasonable to conclude that these binding sites play a role in regulating gene expression. Though not certain, this conclusion is probabilistic. Despite the uncertainty associated with it, the conclusion is still reasonable because a vast body of data demonstrates that transcription factors bind to specific DNA sequences that regulate gene expression. Yes, another explanation for why these transcription factors bind to DNA may exist. Confirmatory experiments can reduce this uncertainty.

The key point is this: there is nothing wrong with concluding, when using inductive reasoning, that sequences that bind transcription factors are functional. By extension, there is nothing wrong with the reasoning the ENCODE Project employed to assign function to sequences in the human genome. The ENCODE Project did not affirm the consequent because they were making use of induction (as do all scientists), not deduction.

It is NOT reasonable to conclude that whenever a transcription factor binds to DNA that site must be a genuine promoter or enhancer. No rational scientist should make that mistake no matter what form of reasoning they employ.

But, to be fair, Rana is in good company since that's exactly what the ENCODE researchers concluded. They assign "function" to every site that bound a transcription factor and they assumed that every bit of DNA that was transcribed has a function.

2. Assigning Function to an Entire Class of Sequence Elements Based on a Few Members

It seems bizarre, but real scientists often discover that one of two pseudogenes or transposons have a function then leap to the conclusion that all pseudogenes and transposons must be functional.

According to Fuz Rana, it is perfectly legitimate to conclude that all pseudogenes and transposons have a function even though only a few have been identified as functional.

In other words, just because researchers identify function for, say, duplicated pseudogenes doesn’t mean all pseudogenes possess function. However, it would be natural in other scientific investigations to assume that if a particular property has been identified for a representative sample, then the entire system possesses that property. Yet when reviewing the ENCODE Project, some evolutionary biologists are eschewing this common practice. Many of the human DNA sequences to which ENCODE assigned function reside within regions of the genome long thought to be junk DNA. It seems Doolittle and others are reluctant to conclude that a part represents the whole due to a pre-commitment to the belief that junk DNA arises via evolutionary processes.

Most pseudogenes and defective transposons have all the hallmarks of broken genes. Therefore, it's logical to assume that all pseudogenes and defective transpsons are non-functional. However, we have now discovered a few exceptions where a pseudogene or a defective transposon has acquired a function. The exceptions prove the rule. What Fuz Rana says makes no sense. You don't assume that all broken genes must have a function just because you discover a few exceptions.

But there's more to his argument. He claims that most of these sequences have been shown to have a function.

The results of the ENCODE Project challenge this evolutionary perspective. The ENCODE team performed a large number of assays, systematically surveying the human genome and cataloging the functional sequences. They didn’t simply identify a few examples of function in particular members of a junk DNA category and then conclude the whole class must be functional. Instead, they identified, one by one, members of a sequence elements group that displayed function.

So, in effect, Doolittle’s complaint holds no weight. It also fails to take into account other work—such as research involving pseudogenes—that not only identifies function for individual members of this junk DNA class, but also presents an elegant framework to explain the function of all members of the category. (Go here and here to read about the competitive endogenous RNA hypothesis as a comprehensive model for pseudogene function.) This type of advance coheres nicely with the catalogue of functional elements ENCODE identified.

This is nonsense. ENCODE did not show that most pseudogenes and defective transposons have a function. At most, they showed that some of them still have promoters and enhancers that bind transcription factors. But that's exactly what we expect of broken genes.

3. Conflating Biochemical Activity with Function

We've been over this ground before. Many of us think that the mere existence of transcripts and DNA binding sites does not indicate function. The biggest mistake made by the ENCODE Consortium was to assume the opposite.

Here's what Fuz Rana says about that ...

To me, this criticism of ENCODE seems motivated by a strong commitment to the evolutionary paradigm. In other words, the experimentally generated ENCODE results don’t square with the expectations of the theory of biological evolution; therefore, the ENCODE results must be wrong. This is an example of theory-dependent reasoning, in which the theoretical framework holds more sway than the actual experimental and observational results. ENCODE skeptics’ commitment to the evolutionary paradigm is so strong it appears that they unwittingly abandoned one of science’s central practices: experimental results dictate a theory’s validity, not the other way around.

These criticisms ignore two important points: (1) biochemical noise costs energy; and (2) random interactions among genome components would be highly deleterious to the organism.

In other words, it's Fuz Rana who is committed to an evolutionary paradigm; namely, adaptationism. He doesn't understand evolution.

I don't know of any theory of biological evolution that predicted junk DNA. This is some kind of fairy tale made up by creationists.

While it’s true that biochemical activity doesn’t necessarily equate to function, the ENCODE researchers appear to have gone to great efforts to ensure that they measured activity with biological meaning. The idea that activities associated with the genome—such as the transcription of the genome, methylation of DNA, modification of histones, binding of transcription factors, and others—are mostly noise borders on the ridiculous because it ignores well-established principles of biochemical operations.

Fuz Rana doesn't understand biochemistry. He should read a textbook in order to learn about "well-established principles of biochemical operations."

4. Squaring with the C-Value Paradox

Most opponents of junk DNA ignore the evidence upon which the concept was founded. I'm referring to the genetic load argument and the C-Value Paradox. The C-Value Paradox refers to the vast range of genome sizes in otherwise similar species. These observations strongly suggest that genome size is unrelated to the number of functional elements in the genome. If two closely related species differ by a factor of two in genome size then most of the DNA in the one with the larger genome must be irrelevant. No other explanation makes sense.

Fuz Rana thinks that most of out genome is functional. That's a problem when we consider less complex organisms that have larger genomes. He has an explanation. In those species, the "extra" DNA performs an additional function that our genome doesn't need. Here's how he describes it ...

In light of the C-value paradox, the ENCODE results would mean that less sophisticated organisms with larger genomes (compared to humans) must also possess more functional elements. But such a scenario makes no sense—at least from an evolutionary perspective. Yet it is possible to account for the larger genomes in organisms less complex than humans. It may be that the excess DNA plays a role other than coding for proteins and regulating gene expression. A number of studies, for example, indicate that DNA dictates the size of the cell nucleus.

So it appears that our genome is full of functional elements that ENCODE can detect but larger genomes just contain "stuffer" DNA. I wonder how he explains complex species, like the pufferfish, that have much smaller genomes?

Fuz Rana concludes that ENCODE skeptics are biased by adherence to some sort of false evolutionary paradigm. He and his colleagues, on the other hand, are much more open-minded so they can follow the evidence wherever it may lead!!!

Despite these latest criticisms, I see no real scientific reason to dismiss the ENCODE Project’s results. Careful consideration reveals that the objections have more to do with philosophy than science. The ENCODE skeptics seem to feel that the ENCODE results must be wrong because they don’t line up with key concepts of the evolutionary paradigm. The ENCODE skeptics even depart from standard scientific practices to maintain their commitment to evolution in the face of the ENCODE discoveries.

The ENCODE Project’s conclusions—namely that at least 80 percent of the human genome is comprised of functional DNA sequences—remain valid evidence for elegant design, befitting the work of a Creator, in the human genome and, by extension, the genomes of other organisms.

1. I'm not sure where in the Bible it says that every bit of the human genome has to be functional. It's been quite a while since I read it. Can anyone supply chapter and verse?

13 comments
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that at least 80 percent of the human genome is comprised of functional DNA sequences—remain valid evidence for elegant design, befitting the work of a Creator, in the human genome and, by extension, the genomes of other organisms.

I wonder what the cutoff point is ?

80% seems to me as if the creator just isn't trying hard enough.

Or perhaps the creator delegated the task to a committee and they fucked up, spent more time deciding on the shape of the table and less on actual design.

And wouldn't a human genome with 0% functional DNA sequences be really, really good evidence for a creator ?

Perhaps our local IDiots and creotards can weigh in and illuminate me.

I wonder if there's another way to persuade reasonable people that the genome cant have greater >80%. The steady state amount of junk should be determined by the rate junk is created minus the rate junk is removed( assuming no selection for or against). Such a calculation would be extremely imprecise, nevertheless, if someone claims the genome has 95% functionality that should require some combination of very low production and very high removal...all of which could be shown to be false.

The steady state amount of junk is not the rate at which junk is created minus the rate at which it is removed. That is the rate at which it increases. Once it has reached its equilibrium level, those two numbers should be equal.

The steady state amount would be the number of bases of junk added per generation, divided by the fraction of junk bases that are deleted each generation. Thus if 10000 bases of junk are added each generation, and each of the existing junk bases has probability 1/1000 of being removed each generation, the the equilibrium amount of junk would be 10000/(1/1000) = 10,000,000 bases.

At that amount the addition (10000) is exactly balanced by the number of bases removed, which is 10000000/1000.

"If two closely related species differ by a factor of two in genome size then most of the DNA in the one with the larger genome must be irrelevant. No other explanation makes sense."

With this opinion are you taking into consideration how variable genome size in closely related species could provide novel insights into species histories? For instance, how do transposable elements contribute to genome evolution?

With this opinion are you taking into consideration how variable genome size in closely related species could provide novel insights into species histories?

Yes.

For instance, how do transposable elements contribute to genome evolution?

Not very much. About 50% of our genome consists of DNA that looks like broken transposons (pseudogenes) and bit & pieces of transposons. In other words, it looks like junk. The default explanation is that it is, indeed, just what it looks like.

I was thinking beyond our own species. For instance the some closely related salamanders have genomes that vary between 15 and 75Gb, most of which is uncharacterized transposable elements. What's a good explanation for a 5x variation in nuclear DNA? Is 75Gb an upper limit or could it go higher?

If giant genomes, depending of course on what they comprise--which we don't know for many species--contribute additively to reproductive isolation and all sorts of morphological features, from cell size to development and metabolism, where do draw the line at junk?

Laurence A. Moran

Larry Moran is a Professor Emeritus in the Department of Biochemistry at the University of Toronto. You can contact him by looking up his email address on the University of Toronto website.

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The Sandwalk is the path behind the home of Charles Darwin where he used to walk every day, thinking about science. You can see the path in the woods in the upper left-hand corner of this image.

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Quotations

The old argument of design in nature, as given by Paley, which formerly seemed to me to be so conclusive, fails, now that the law of natural selection has been discovered. We can no longer argue that, for instance, the beautiful hinge of a bivalve shell must have been made by an intelligent being, like the hinge of a door by man. There seems to be no more design in the variability of organic beings and in the action of natural selection, than in the course which the wind blows.Charles Darwin (c1880)Although I am fully convinced of the truth of the views given in this volume, I by no means expect to convince experienced naturalists whose minds are stocked with a multitude of facts all viewed, during a long course of years, from a point of view directly opposite to mine. It is so easy to hide our ignorance under such expressions as "plan of creation," "unity of design," etc., and to think that we give an explanation when we only restate a fact. Any one whose disposition leads him to attach more weight to unexplained difficulties than to the explanation of a certain number of facts will certainly reject the theory.

Charles Darwin (1859)Science reveals where religion conceals. Where religion purports to explain, it actually resorts to tautology. To assert that "God did it" is no more than an admission of ignorance dressed deceitfully as an explanation...

Quotations

The world is not inhabited exclusively by fools, and when a subject arouses intense interest, as this one has, something other than semantics is usually at stake.
Stephen Jay Gould (1982)
I have championed contingency, and will continue to do so, because its large realm and legitimate claims have been so poorly attended by evolutionary scientists who cannot discern the beat of this different drummer while their brains and ears remain tuned to only the sounds of general theory.
Stephen Jay Gould (2002) p.1339
The essence of Darwinism lies in its claim that natural selection creates the fit. Variation is ubiquitous and random in direction. It supplies raw material only. Natural selection directs the course of evolutionary change.
Stephen Jay Gould (1977)
Rudyard Kipling asked how the leopard got its spots, the rhino its wrinkled skin. He called his answers "just-so stories." When evolutionists try to explain form and behavior, they also tell just-so stories—and the agent is natural selection. Virtuosity in invention replaces testability as the criterion for acceptance.
Stephen Jay Gould (1980)
Since 'change of gene frequencies in populations' is the 'official' definition of evolution, randomness has transgressed Darwin's border and asserted itself as an agent of evolutionary change.
Stephen Jay Gould (1983) p.335
The first commandment for all versions of NOMA might be summarized by stating: "Thou shalt not mix the magisteria by claiming that God directly ordains important events in the history of nature by special interference knowable only through revelation and not accessible to science." In common parlance, we refer to such special interference as "miracle"—operationally defined as a unique and temporary suspension of natural law to reorder the facts of nature by divine fiat.
Stephen Jay Gould (1999) p.84

Quotations

My own view is that conclusions about the evolution of human behavior should be based on research at least as rigorous as that used in studying nonhuman animals. And if you read the animal behavior journals, you'll see that this requirement sets the bar pretty high, so that many assertions about evolutionary psychology sink without a trace.

Jerry Coyne
Why Evolution Is TrueI once made the remark that two things disappeared in 1990: one was communism, the other was biochemistry and that only one of them should be allowed to come back.

Sydney Brenner
TIBS Dec. 2000
It is naïve to think that if a species' environment changes the species must adapt or else become extinct.... Just as a changed environment need not set in motion selection for new adaptations, new adaptations may evolve in an unchanging environment if new mutations arise that are superior to any pre-existing variations

Douglas Futuyma
One of the most frightening things in the Western world, and in this country in particular, is the number of people who believe in things that are scientifically false. If someone tells me that the earth is less than 10,000 years old, in my opinion he should see a psychiatrist.

Francis Crick
There will be no difficulty in computers being adapted to biology. There will be luddites. But they will be buried.

Sydney Brenner
An atheist before Darwin could have said, following Hume: 'I have no explanation for complex biological design. All I know is that God isn't a good explanation, so we must wait and hope that somebody comes up with a better one.' I can't help feeling that such a position, though logically sound, would have left one feeling pretty unsatisfied, and that although atheism might have been logically tenable before Darwin, Darwin made it possible to be an intellectually fulfilled atheist

Richard Dawkins
Another curious aspect of the theory of evolution is that everybody thinks he understand it. I mean philosophers, social scientists, and so on. While in fact very few people understand it, actually as it stands, even as it stood when Darwin expressed it, and even less as we now may be able to understand it in biology.

Jacques Monod
The false view of evolution as a process of global optimizing has been applied literally by engineers who, taken in by a mistaken metaphor, have attempted to find globally optimal solutions to design problems by writing programs that model evolution by natural selection.